Impact of lamivudine-resistance mutations on entecavir treatment outcome in hepatitis B.

BACKGROUND AND OBJECTIVE: Entecavir (ETV) is a potent inhibitor of viral replication in nucleos(t)ide analog (NA)-naive chronic hepatitis B patients with a very low rate of resistance (≤1.2%) over 5 years. The aim of this study was to assess the efficacy of ETV treatment in routine clinical practice and to investigate whether persistence of residual viral replication was the result of the emergence and selection of drug-resistant mutants. PATIENTS AND METHODS: Chronic hepatitis B patients treated with ETV were consecutively recruited from the Department of Hepatology, Hospices Civils de Lyon, France, and were monitored regularly within their routine clinical follow-up. Virological, biochemical, clinical, and tolerance findings were assessed prospectively. RESULTS: A total of 79 patients were studied, of whom 58% received ETV as a first-line therapy. During ETV therapy (median follow-up 42 months), hepatitis B virus (HBV) DNA became undetectable in 95% of patients. Time to HBV DNA undetectability was significantly shorter in patients with an HBV DNA level less than 4 log10 IU/ml at baseline and in HBeAg-negative patients. Moreover, time to undetectability was significantly shorter in patients with no or only one lamivudine-resistance (LAMr) mutation than in patients with two or more LAMr mutations (P=0.050). No patient had renal-function impairment during ETV therapy. CONCLUSION: In routine clinical practice, ETV is effective in both NA-naive and NA-experienced patients, except in patients with HBV strains harboring at least two LAMr mutations. The analysis of viral genome sequence at the time of treatment adaptation could prove useful to personalize antiviral therapy in patients failing a previous line of treatment.

Clearance of serum HBsAg and anti-HBs seroconversion following antiviral therapy for chronic hepatitis B.

In this study, we have analyzed the evolution of serum HBsAg levels in 16 patients with chronic hepatitis B who showed an HBsAg seroconversion following antiviral therapy. The data showed that the clearance of serum HBsAg is slower than that of serum HBV DNA, which may reflect a slow kinetics of clearance of infected hepatocytes. Interestingly, HBsAg was detectable for a longer time using the Architect assay than with the Bio-Rad assay. As viremia suppression is achieved in most patients under therapy with the new generation of nucleoside analogs, these data suggest that the quantitative monitoring of serum HBsAg may represent a novel tool for the assessment of antiviral therapy efficacy.

Immunohistochemical detection of HCV proteins in liver tissue.

Detection and localization of HCV in liver tissue are vital for diagnostic purposes and clinical management of HCV-infected patients, as well as for the elucidation of viropathological mechanisms. The fragility of HCV RNA and the low levels of viral expression in infected tissues are a constant limitation in molecular assays for HCV characterization. HCV antigen detection, by immunochemistry, in liver biopsies is an attractive option for precise localization and quantification of viral proteins with direct access to histological patterns. We describe here a study using a novel immunohistochemical method effective on fixed, archived specimens, including liver biopsies and surgical resection samples. The initial protocol uses a biotin-detection system but can also be used in a polymer-detection system. This protocol offers easy, precise, and strong staining resolution with distinct patterns consistent with the liver pathology, irrespective of the viral HCV genotype examined. This approach provides applications for diagnosis as well as for exploratory pathological studies.

Long-term antiviral therapy for recurrent hepatitis C after liver transplantation in nonresponders: biochemical, virological, and histological impact.

More than 50% of patients with a recurrent posttransplant hepatitis C virus infection fail to respond to antiviral treatment. The aim of this study was to evaluate the interest of a long-term antiviral treatment maintained for more than 48 weeks. Seventy treated patients, with a histological follow-up > 1 year, were enrolled in this observational, retrospective study. The duration of antiviral treatment, tolerance, and occurrence of virological, biochemical, and histological responses were recorded. Thirty-two patients were nonresponders after 48 weeks of treatment. Combined antiviral therapy was maintained for >12 months in 26 and for >18 months in 21. Twelve patients had to discontinue their treatment. At 48 weeks, the rates of virological response and sustained virological response were 37% and 24.3%, respectively; at the end of the follow-up, they were 48.5% and 35.7%. Virological response was significantly associated with a higher incidence of biochemical and histological response, regardless of its time of occurrence (before or after 6 months). Even in the absence of virological response, the rate of progression of fibrosis was significantly slowed in patients treated for more than 6 months. Our results show the feasibility, safety, and efficacy of long-term antiviral therapy in nonresponder patients with a recurrent posttransplant hepatitis C virus infection.

Impact of highly active antiretroviral therapy (HAART) on the natural history of hepatitis B virus (HBV) and HIV coinfection: relationship between prolonged efficacy of HAART and HBV surface and early antigen seroconversion.

BACKGROUND: Coinfection with hepatitis B virus (HBV) in human immunodeficiency virus (HIV)-infected patients is common. However, little is known about the natural history of chronic hepatitis B in HIV-infected populations, especially the impact of highly active antiretroviral therapy (HAART) on the outcome of HBV early antigen (HBeAg) and HBV surface antigen (HBsAg) status. METHODS: The characteristics of 92 patients coinfected with HIV and HBV were retrospectively assessed before and after HAART and lamivudine treatment to determine the impact of treatment on chronic hepatitis B and factors associated with HBeAg and/or HBsAg seroconversion. RESULTS: During follow-up, 82 patients received antiretroviral therapy, 79 of whom received HAART. Twenty-eight of the 76 patients who were administered lamivudine therapy developed lamivudine resistance mutations. While receiving antiretroviral therapy, 10 of 59 HBeAg-positive patients developed antibody to HBeAg, 3 of 10 cleared HBsAg, and 2 of 3 developed antibody to HBsAg. Two of 23 HBeAg-negative patients cleared HBsAg and developed antibody to HBsAg. HBeAg and/or HBsAg seroconversion combined with an undetectable HBV DNA level (i.e., an HBV response) correlated with a sustained HIV response (P=.001), shorter duration of antiretroviral therapy (P=.058), and more-severe disease, as evaluated by Centers for Disease Control and Prevention staging (for stage B vs. stage A, P=.029; for stage C vs. stage A, P=.069). For patients with elevated baseline alanine aminotransferase levels, the HBV response correlated significantly with a greater increase in CD4 cell count while receiving HAART. CONCLUSIONS: In HIV-HBV-coinfected patients, HBV response correlated with a sustained HIV response to antiretroviral therapy, usually HAART including lamivudine.

Efficient hepatitis C antigen immunohistological staining in sections of normal, cirrhotic and tumoral liver using a new monoclonal antibody directed against serum-derived HCV E2 glycoproteins.

Detection and localization of Hepatitis C Virus (HCV) in liver tissue is useful for diagnostic purposes as well as to elucidate the mechanisms by which the virus participates in hepatocarcinogenesis. However, so far, a sensitive method for HCV detection at the cellular level is lacking. We describe here the application of a novel antibody, D4.12.9, developed against serum-derived HCV RNA-positive particles, for the detection of E2 proteins by immunohistochemistry in fixed, archived specimens including liver biopsies of HCV-infected patients and surgical specimens of hepatocellular carcinoma. We demonstrate that D4.12.9 is a powerful tool for sensitive and specific detection of HCV, independently of viral genotype. This approach has applications to diagnosis as well as exploratory pathological studies.

Successful cardiac resynchronization therapy after cardiac surgery.

Cardiac resynchronization therapy improves symptoms and survival in chronic heart failure patients, but has been poorly studied in the acute heart failure setting. We report the case of successful cardiac resynchronization therapy in the early postoperative period after cardiac surgery in a patient with left bundle branch block and proven ventricular dyssynchrony.

Follow-up and management of patients exposed to a flawed automated endoscope washer-disinfector in a digestive diseases unit.

The possible transmission of pathogens to 236 persons exposed to an endoscope processed in a flawed automated endoscope washer-disinfector in a gastrointestinal endoscopy unit was investigated. During 6 months, 197 patients (83.5%) were followed up, and no cases of acute human immunodeficiency virus, hepatitis C virus, or hepatitis B virus infection were observed. This event created the conditions for improvements in safety procedures.

Sustained HBs seroconversion during lamivudine and adefovir dipivoxil combination therapy for lamivudine failure.

We describe the case of a patient with chronic hepatitis B who became resistant to lamivudine and was treated successfully with adefovir dipivoxil in addition to lamivudine. Lamivudine resistance was associated with the selection of a L180M+M204V polymerase mutant. After the addition of adefovir dipivoxil, serum HBV DNA levels dropped by more than 4log(10), which was followed by HBsAg clearance after 22 months of combination therapy. Moreover, anti-HBs antibody titers rose above 1000 mIU/mL after 32 months of the new treatment regimen. In parallel, HBV DNA declined below 100 copies/mL by a quantitative real time PCR assay. Analysis of intrahepatic viral DNA showed a significant decline of total HBV DNA and cccDNA which was accompanied by a decrease of the number of infected cells expressing viral antigens below the detection limit of immunostaining. In parallel, liver histology analysis showed an improvement in both the activity index and fibrosis score. This report suggests that in patients who previously failed lamivudine therapy, proactive antiviral treatment may lead to a beneficial virological and clinical effect.

Treatment of recurrent hepatitis C after liver transplantation: a pilot study of peginterferon alfa-2b and ribavirin combination.

BACKGROUND/AIMS: After liver transplantation (LT) for HCV-related cirrhosis, recurrence of HCV infection is universal and the risk of progression to cirrhosis is high. The modalities and efficacy of antiviral therapy in this indication are still controversial. We present here the results of a pilot study of a 12-month combination therapy by pegylated alfa 2b-interferon (PEG-IFN) and ribavirin in 20 patients. METHODS: Twenty patients entered the study (13 male and 7 female, median age 53.8 years). In 80% of patients, HCV infection was of genotype 1. The delay between LT and antiviral therapy was 28 months. The doses were progressively increased from 0.5 to 1 micro g/kg/week for PEG-IFN and from 400 to 1000-1200 mg/d for ribavirin. Follow-up was based on biochemical (ALT), virological (HCV-RNA) and histological (liver biopsy) examinations. RESULTS: Four patients (20%) were withdrawn due to adverse effects. In 6 patients the dose of PEG-IFN had to be reduced to 0.5 micro g/kg/week. A reduction in the dose of ribavirin in 13/16 cases was due to the onset of anemia. Histological evidence of mild acute rejection increased the immunosuppressive regimen in 5/20 patients. At the end of the treatment, 75% of the patients had a biochemical response and 55% a virological response. The mean METAVIR score, according to activity and fibrosis, was A1.8 F2.2 before treatment and A0.3 F1.6 at the end of treatment. In 9/20 patients, virological response persisted 6 months after the end of the treatment. CONCLUSIONS: Our results suggest that combination therapy by PEG-IFN and ribavirin may be well tolerated and beneficial during recurrent hepatitis C in liver transplant recipients.

Combined lamivudine and hepatitis B immunoglobulin for the prevention of hepatitis B recurrence after liver transplantation: long-term results.

For the prevention of recurrent hepatitis B virus (HBV) infection after liver transplantation (LT), the efficacy of hepatitis B immunoglobulin (HBIg) has been largely demonstrated. The aim of this pilot study was to determine if the addition of lamivudine to HBIg in the prevention of HBV recurrence after LT could be more effective. Sixty HBsAg-positive/HBV DNA-negative patients underwent LT from October 1990 to December 2001. All 60 patients received intravenous HBIg to maintain serum anti-HB levels above 500 IU/L, indefinitely. Since 1997, 17 patients have received combined oral lamivudine (150 mg/day) and HBIg, and were compared with the historical cohort of 43 patients. In the historical control group, the recurrence rate was 10/43 (23%) after a 98-month median follow-up. Five patients died from HBV-related liver disease. After a 30-month median follow-up, none of the 17 patients in the combined prophylaxis group experienced HBV recurrence, and HBV DNA was undetectable by PCR in at least three serum samples per patient. HBV recurrence was significantly lower when compared with the historical control group (10/43 vs. 0/17, p < 0.01). Our results suggest that combined lamivudine and HBIg can avoid the recurrence of HBV infection in patients who are HBsAg-positive/HBV DNA negative before LT.

[Early treatment of acute hepatitis C with interferon alpha-2b or interferon alpha-2b plus ribavirin: study of sixteen patients]. / Etude de seize cas d'hépatite C aiguë. Essai de traitement précoce par l'interféron alpha- 2b ou interféron alpha- 2b et ribavirine.

AIM OF THE STUDY: To assess the mode of transmission and the efficacy of antiviral therapy in the outcome of treated and untreated patients with acute hepatitis C. PATIENTS AND METHODS: From December 1995 to January 2001, 16 consecutive patients and their response to therapy were studied, including clinical, biochemical, virological and histological data. RESULTS: Hepatitis C virus (HCV) exposure was IVDU (38%), needle-stick injury (19%), medical procedure (6%), piercing (6%), suspected sexual contact (19%), and unknown in 2. Among 13 patients treated for acute hepatitis C, all 12 patients who completed therapy had a biochemical and virological sustained response for more than 15 months (range: 4-36 months) after stopping therapy. Therapy was tolerated in all but one patient, who stopped after 10 weeks because of side effects. Duration of treatment, type of interferon and combination with ribavirin did not modify the response to treatment. CONCLUSION: These results suggest that early intervention with interferon alpha is effective in preventing the progression of acute HCV infection to chronic hepatitis in most patients regardless of duration, type of interferon, or combination with ribavirin.

Effects of co-infection with hepatitis C virus and GB virus C on CD4 cell count and HIV-RNA level among HIV-infected patients treated with highly active antiretroviral therapy.

The effects of co-infection with hepatitis C virus (HCV) and GB virus C (GBV-C) on CD4 cell counts and plasma HIV-RNA levels has been investigated in HIV-infected patients treated with highly active antiretroviral therapy (HAART). Patients co-infected with HCV and GBV-C experienced a CD4 cell increase during 4 years of HAART, whereas the increase stopped after 2 years in the other groups.